Evolutionary ChemistryTM (EC) is a potentially revolutionary approach to the discovery of lead small molecule pharmaceuticals. EC integrates the steps of small molecule synthesis and high throughput screening into a single system. By utilizing the demonstrated ability of RNA to catalyze chemical transformations that can create drug-like molecules, an enormous small molecule chemical library can be assembled that contains one hundred thousand to one billion potential lead compounds. Through iterative cycles of small molecule library assembly, evolutionary pressure and biocatalyst amplification, compounds that best perform a desired function are identified. We propose to apply the EC methodology to the validated HIV drug target, aspartyl protease, because of the urgent need for new HIV therapies and because success through this approach would demonstrate the advantages of EC: a methodology capable of completely surveying the small molecule/protein interface around already successful core structures and of demanding that selected compounds exhibit prescribed properties. Importantly, evolutionary pressures applied during the partitioning component of EC will increase the likelihood that the HIV protease inhibitor drug leads that are identified will be active against clinical isolates resistant to current therapies, as well as increasing the probability that these compounds will have favorable bioavailability and metabolic stability.